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Summary Transfusion support is an essential element of modern emergency healthcare. Blood services together with hospital transfusion teams are required to prepare for, and respond to, mass casualty events as part of wider healthcare emergency planning. Preparedness is a constant collaborative process that actively identifies and manages potential risks, to prevent such events becoming a ‘disaster'. The aim of transfusion support during incidents is to provide sufficient and timely supply of blood components and diagnostic services, whilst maintaining support to other patients not involved in the event.

Background Preparatory, written plans for mass casualty incidents are designed to help hospitals deliver an effective response. However, addressing the frequently observed mismatch between planning and delivery of effective responses to mass casualty incidents is a key challenge. We aimed to use simulation-based iterative learning to bridge this gap. Methods We used Normalisation Process Theory as the framework for iterative learning from mass casualty incident simulations. Five small-scale ‘focused response' simulations generated learning points that were fed into two large-scale whole-hospital response simulations. Debrief notes were used to improve the written plans iteratively. Anonymised individual online staff surveys tracked learning. The primary outcome was system safety and latent errors identified from group debriefs. The secondary outcomes were the proportion of completed surveys, confirmation of reporting location, and respective roles for mass casualty incidents. Results Seven simulation exercises involving more than 700 staff and multidisciplinary responses were completed with debriefs. Usual emergency care was not affected by simulations. Each simulation identified latent errors and system safety issues, including overly complex processes, utilisation of space, and the need for clarifying roles. After the second whole hospital simulation, participants were more likely to return completed surveys (odds ratio=2.7; 95% confidence interval [CI], 1.7–4.3). Repeated exercises resulted in respondents being more likely to know where to report (odds ratio=4.3; 95% CI, 2.5–7.3) and their respective roles (odds ratio=3.7; 95% CI, 2.2–6.1) after a simulated mass casualty incident was declared. Conclusion Simulation exercises are a useful tool to improve mass casualty incident plans iteratively and continuously through hospital-wide engagement of staff.

Supplementary Legends for Figures 1-5, Tables 1-3 from Identification of PDE4D as a Proliferation Promoting Factor in Prostate Cancer Using a Sleeping Beauty Transposon-Based Somatic Mutagenesis Screen

Supplementary Figures 1-5, Tables 1-3 from Identification of PDE4D as a Proliferation Promoting Factor in Prostate Cancer Using a Sleeping Beauty Transposon-Based Somatic Mutagenesis Screen

Background There is renewed interest in the use of whole blood (WB) for the resuscitation of trauma patients. Platelet function in stored WB compared to platelet concentrates is not well established and was assessed in vitro in this study. Methods Leucocyte-depleted cold-stored WB (CS-WB) was prepared using a Terumo WB-SP Imuflex kit and held at 2-6°C alongside: (A) UK standard pooled platelets stored at 20-24°C (RT-PLTS), (B) pooled platelets stored at 2-6°C (CS-PLTS), and (C) platelet-rich plasma produced using the Terumo kit (CS-PRP), for 21 days. A series of in vitro assays were assessed platelet function. Results Platelet count was retained to 57 ± 14% of starting number at day 21 in CS-WB. Over time, CS-WB platelets become more activated, with increased CD62P expression (day 1: 7 ± 3.7% vs. day 21: 59 ± 17.1%) and annexin V binding (day 1: 2 ± 0.2% vs. day 21: 21 ± 15.1%). For comparison, 18.6 ± 6% of platelets in RT-PLTS demonstrated CD62P expression at day 7, whereas annexin V binding in RT-PLTS at day 7 was 2.6 ± 0.5%. Over storage, aggregatory response to agonists decreased in all arms. Functional platelet microparticles increased steadily in CS-WB throughout storage. Conclusion During storage, platelet count reduced in CS-WB, whereas CD62P expression and annexin V binding increased. This was accompanied by a reduced aggregatory response, although compared to 7-day-old RT-PLTS, CS-WB maintained a maximal response to agonists for longer, suggesting that the shelf life for CS-WB can be considered for up to 21 days.

While massive transfusion (MT) recipients account for a small proportion of all transfused patients, they account for approximately 10% of blood products issued. Furthermore, MT events pose organizational and logistical challenges for health care providers, laboratory and transfusion services. Overall, the majority of MT events are to support major bleeding in surgical patients, trauma and gastrointestinal hemorrhage. The clinical context in which the bleeding event occurred, the number of blood products required, patient age and comorbidities are the most important predictors of outcomes for short- and long-term survival. These data are important to inform blood services, clinicians and health care providers in order to improve care and outcomes for patients with major bleeding. There is no standard accepted definition of MT, with most definitions based on number of blood components administered within a certain time-period or activation of MT protocol. The type of definition used has implications for the clinical characteristics of MT recipients included in epidemiological and interventional studies. In order to understand trends in incidence of MT, variation in blood utilization and patient outcomes, and to harmonize research outcomes, a standard and universally accepted definition of MT is urgently required.

BACKGROUND Trial outcomes should be relevant to all stakeholders and allow assessment of interventions' efficacy and safety at appropriate timeframes. There is no consensus regarding outcome measures in the growing field of prehospital trauma transfusion research. Harmonization of future clinical outcome reporting is key to facilitate interstudy comparisons and generate cohesive, robust evidence to guide practice. The objective of this study was to evaluate outcome measures reported in prehospital trauma transfusion trials. METHODS Data Sources, Eligibility Criteria, Participants, and InterventionsWe conducted a scoping systematic review to identify the type, number, and definitions of outcomes reported in randomized controlled trials, and prospective and retrospective observational cohort studies investigating prehospital blood component transfusion in adult and pediatric patients with traumatic hemorrhage. Electronic database searching of PubMed, Embase, Web of Science, Cochrane, OVID, clinical trials.gov, and the Transfusion Evidence Library was completed in accordance with Preferred Reporting Items for Meta-analyses guidelines.Study Appraisal and Synthesis MethodsTwo review authors independently extracted outcome data. Unique lists of salutogenic (patient-reported health and wellbeing outcomes) and nonsalutogenic focused outcomes were established. RESULTS A total of 3,471 records were identified. Thirty-four studies fulfilled the inclusion criteria: 4 military (n = 1,566 patients) and 30 civilian (n = 14,398 patients), all between 2000 and 2020. Two hundred twelve individual non-patient-reported outcomes were identified, which collapsed into 20 outcome domains with varied definitions and timings. All primary outcomes measured effectiveness, rather than safety or complications. Sixty-nine percent reported mortality, with 11 different definitions. No salutogenic outcomes were reported. CONCLUSION There is heterogeneity in outcome reporting and definitions, an absence of patient-reported outcome, and an emphasis on clinical effectiveness rather than safety or adverse events in prehospital trauma transfusion trials. We recommend stakeholder consultation and a Delphi process to develop a clearly defined minimum core outcome set for prehospital trauma transfusion trials. LEVEL OF EVIDENCE Scoping systematic review, level III.

BACKGROUND Early plasma transfusion for management of bleeding, particularly trauma, is associated with better outcomes. Improving the availability/safety of plasma transfusion for patients is essential for transfusion services. The aim of this study is to evaluate the hemostatic capacity of methylene-blue (MB) liquid (not frozen) plasma over time. MATERIALS AND METHODS Twenty whole blood-derived plasma units collected from male donors were separated and processed within 18 h of collection. Individual plasmas were treated with MB and stored in liquid status at 2-6°C for 14 days. A range of coagulation assays, including thrombin generation, rotational thromboelastometry (ROTEM), and Thrombodynamics were tested at different time-points, together with bacterial growth. RESULTS Apart from Factor (F)XII, other coagulation factors (fibrinogen, FV, FVIII, FXI) reduced significantly after MB treatment, with levels remaining stable except for FVIII afterward. By day 14, most clotting factors were >0.7 IU/ml, apart from FVIII. There was a disproportionate decrease in Protein S (PS) activity compared to free PS antigen and by day 14 its value was ~50%. There was no significant difference in maximum clot formation (ROTEM) and clot-density (Thrombodynamics) over time. Endogenous thrombin potential (Thrombin-Generation), clot-size, and velocity index (Thrombodynamics) decreased significantly over time consistent with clotting factor reduction. There was no bacterial growth. CONCLUSIONS MB-treated liquid plasma stored at 2-6°C can be used for up to 14 days: the long shelf-life, the liquid status, and the MB treatment will improve its availability for management of bleeding as well as providing a safe component from pathogens.

Summary The emerging COVID‐19 pandemic has overwhelmed healthcare resources worldwide, and for transfusion services this could potentially result in rapid imbalance between supply and demand due to a severe shortage of blood donors. This may result in insufficient blood components to meet every patient's needs resulting in difficult decisions about which patients with major bleeding do and do not receive active transfusion support. This document, which was prepared on behalf of the National Blood Transfusion Committee in England, provides a framework and triage tool to guide the allocation of blood for patients with massive haemorrhage during severe blood shortage. Its goal is to provide blood transfusions in an ethical, fair, and transparent way to ensure that the greatest number of life years are saved. It is based on an evidence‐ and ethics‐based Canadian framework, and would become operational where demand for blood greatly exceeds supply, and where all measures to manage supply and demand have been exhausted. The guidance complements existing national shortage plans for red cells and platelets.

Fibrinogen levels drop early in postpartum hemorrhage (PPH), and low fibrinogen levels predict outcomes. There is increasing interest in replacing fibrinogen early in severe PPH and this systematic review's aim was to assess if early fibrinogen replacement therapy improves outcomes in severe PPH. We searched the following databases from inception to June 2019: CDSR and CENTRAL (The Cochrane Library), MEDLINE, Embase, CINAHL, PubMed, Transfusion Evidence Library, LILACS, Web of Science Conference Proceedings Citation Index-Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Portal. We included randomized (RCT) and well-designed controlled observational studies where fibrinogen replacement therapy was given early (within 90 minutes of bleeding) compared with standard protocol in pregnant women > 24 weeks' gestation who developed PPH, defined as estimated blood loss ≥500 mL up to 24 hours post-delivery. Two independent reviewers extracted and reviewed the data on the primary outcome of allogeneic blood transfusion at 24 hours after intervention and secondary outcomes including all-cause mortality, rate of thrombosis, and the need for surgical and non-surgical interventions. We identified 5 eligible studies: 2 completed (total of 299 women) RCTs comparing fibrinogen concentrate with placebo, and 3 ongoing RCTs. There was no completed study assessing cryoprecipitate transfusion. There was variation of: timings of intervention administration; severity of PPH; fibrinogen doses and use of tranexamic acid. There was insufficient evidence that early administration of fibrinogen in PPH reduces the need for allogeneic blood transfusion at 24 hours (risk ratio 0.83 (95% CI 0.54-1.26), P = 0.38) (2 trials, 299 participants) or improves other outcomes. Both studies were underpowered to answer our outcomes. There is a lack of evidence that early fibrinogen replacement therapy improves outcomes in PPH. Future studies are needed to address this, underpinned by data on the optimal fibrinogen dose, protocol-driven approaches versus targeted therapy, and cost-effectiveness of cryoprecipitate versus fibrinogen concentrate therapy in PPH.

Objectives In 2015, three London cardiac centres, with different transfusion infrastructure support, merged to form the Barts Heart Centre. We describe the impact on transfusion rate, blood usage and interoperator variation. Design Data was collected on all adult patients undergoing cardiac surgery during 2014 as well as 2016, using the National Institute Cardiovascular Outcomes Research (NICOR) data set. Measurements and main results Over the two time periods, a total of 3,647 cardiac procedures were performed (1,930 in 2014 and 1,717 in 2016). There were no significant differences in type of surgery or patient comorbidity between the two epochs of time. Overall, red blood cell transfusion at 24 hours and until hospital discharge reduced significantly in 2016 (odds ratio 0.77; 95% confidence interval 0.68–0.89; p=0.0002). Interoperator variability (adjusted for comorbidities) reduced after merger from standard deviation 0.394 (standard error (SE) 0.096) to 0.269 (SE 0.082), p=0.001. Conclusion Clinical and organisational factors can improve transfusion service.

Footrot has a major impact on health and productivity of sheep worldwide. The current paradigm for footrot pathogenesis is that physical damage to the interdigital skin (IDS) facilitates invasion of the essential pathogen Dichelobacter nodosus. The composition of the IDS microbiota is different in healthy and diseased feet, so an alternative hypothesis is that changes in the IDS microbiota facilitate footrot. We investigated the composition and diversity of the IDS microbiota of ten sheep, five that did develop footrot and five that did not (healthy) at weekly intervals for 20 weeks. The IDS microbiota was less diverse on sheep 2 + weeks before they developed footrot than on healthy sheep. This change could be explained by only seven of > 2000 bacterial taxa detected. The incubation period of footrot is 8–10 days, and there was a further reduction in microbial diversity on feet that developed footrot in that incubation period. We conclude that there are two stages of dysbiosis in footrot: the first predisposes sheep to footrot and the second occurs in feet during the incubation of footrot. These findings represent a step change in our understanding of the role of the IDS microbiota in footrot pathogenesis.

Our aim was to assess whether there is a difference in outcomes of potential “all-cause” harm in the transfusion of whole blood (WB) compared to blood components (BC) for any bleeding patient regardless of age or clinical condition. We searched multiple electronic databases using a pre-defined search strategy from inception to 2ndMarch 2021. 1 reviewer screened, extracted, and analysed data, with verification by a second reviewer of all decisions. We used Cochrane ROB1 and GRADE to assess the quality of the evidence. We used predefined subgroups of trauma and non-trauma studies in the analysis. We included six RCTs (618 participants) which compared WB and BCtransfusion therapyin major bleeding, one trauma trial (n=107), and 5 surgical trials (non-trauma) (n=511). We GRADED evidence as very-low for all outcomes (downgraded for high and unclear risk of bias, small sample size, and wide confidence intervals around the estimate). Our primary outcome (all-cause mortality at 24-hours and 30-days) was reported in 3 out of 6 included trials. There was no evidence of a difference in mortality of WB compared to BC therapy (very-low certainty evidence). There may be a benefit of WB therapy compared to BC therapy in the non-trauma subgroup, with a reduction in the duration of oxygen dependence (1 study;n=60; mean difference 5.9 fewer hours [95% Confidence Interval [CI] -10.83, –0.99] in WB group), and a reduction in hospital stay (1 study,n=64, median difference 6 fewer days in WB group) (very-low certainty evidence). For the remaining outcomes (organ injury,mechanical ventilationand intensive care unit requirement, infection, arterial/venous thrombotic events, and haemolytic transfusion reaction) there was no difference between WB and BC therapy (wide CI, crossing line of no effect), though many of these outcomes were based on small single studies (very-low certainty evidence). In conclusion, there appears to be little to no difference in harms between WB and BC therapy, based on small studies with very low certainty of the evidence. Further large trials are required to establish the overall safety of WB compared to BC, and to assess differences between trauma and non-trauma patients.

Surgical site infections (SSI) cause substantial morbidity and pose a burden to acute healthcare services after surgery. We aimed to investigate whether a smartphone-delivered wound assessment tool can expedite diagnosis and treatment of SSI after emergency abdominal surgery. This single-blinded randomised control trial (NCT02704897) enroled adult emergency abdominal surgery patients in two tertiary care hospitals. Patients were randomised (1:1) to routine postoperative care or additional access to a smartphone-delivered wound assessment tool for 30-days postoperatively. Patient-reported SSI symptoms and wound photographs were requested on postoperative days 3, 7, and 15. The primary outcome was time-to-diagnosis of SSI (Centers for Disease Control definition). 492 patients were randomised (smartphone intervention: 223; routine care: 269). There was no significant difference in the 30-day SSI rate between trial arms: 21 (9.4%) in smartphone vs 20 (7.4%, p = 0.513) in routine care. Among the smartphone group, 32.3% (n = 72) did not utilise the tool. There was no significant difference in time-to-diagnosis of SSI for patients receiving the intervention (−2.5 days, 95% CI: −6.6−1.6, p = 0.225). However, patients in the smartphone group had 3.7-times higher odds of diagnosis within 7 postoperative days (95% CI: 1.02−13.51, p = 0.043). The smartphone group had significantly reduced community care attendance (OR: 0.57, 95% CI: 0.34−0.94, p = 0.030), similar hospital attendance (OR: 0.76, 95% CI: 0.28−1.96, p = 0.577), and significantly better experiences in accessing care (OR: 2.02, 95% CI: 1.17−3.53, p = 0.013). Smartphone-delivered wound follow-up is feasible following emergency abdominal surgery. This can facilitate triage to the appropriate level of assessment required, allowing earlier postoperative diagnosis of SSI.

Footrot has a major impact on health and productivity of sheep worldwide. The current paradigm for footrot pathogenesis is that physical damage to the interdigital skin (IDS) facilitates invasion of the essential pathogen Dichelobacter nodosus. The composition of the IDS microbiota is different in healthy and diseased feet, so an alternative hypothesis is that changes in the IDS microbiota facilitate footrot. We investigated the composition and diversity of the IDS microbiota of ten sheep, five that did develop footrot and five that did not (healthy) at weekly intervals for 20 weeks. The IDS microbiota was less diverse on sheep 2+ weeks before they developed footrot than on healthy sheep. This change could be explained by only seven of >2000 bacterial taxa detected. The incubation period of footrot is 8-10 days, and there was a further reduction in microbial diversity on feet that developed footrot in that incubation period. We conclude that there are two stages of dysbiosis in footrot: the first predisposes sheep to footrot and the second occurs in feet during the incubation of footrot. These findings change the paradigm of footrot pathogenesis.

AprV2andaprB2are variants of the apr gene ofDichelobacter nodosus, the cause of footrot in sheep. They are putative markers for severe and mild disease expression. The aim of our study was to investigate the distribution ofaprV2andaprB2in flocks with and without footrot. Our hypotheses were that both strains are present in endemically affected flocks, withaprB2andaprV2associated with mild and virulent phenotypes respectively but thatD. nodosusis not present in flocks without footrot. Alternatively,aprB2persists in flocks without footrot. Despite extensive searching over 3 years only three flocks of sheep without footrot were identified.D. nodosuswas not detected in these three flocks. In one further flock, only mild interdigital dermatitis was observed, and onlyaprB2was detected. Twenty-four flocks with endemic footrot of all severities were sampled on three occasions and all were positive forD. nodosusand theaprV2variant;aprB2was detected in only 11 of these flocks.AprB2was detected as a co-infection withaprV2in the 22% of samples positive foraprB2and was more likely in mild footrot phenotypes than severe.Dichelobacter nodosusserogroups were not associated with footrot phenotype. We conclude thatD. nodosus, evenaprB2strains, do not persist in flocks in the absence of footrot. Our results support the hypothesis thataprB2is associated with mild footrot phenotypes. Finally, we conclude that given the small number of flocks without footrot that were identified, footrot is highly endemic in English sheep flocks.

Recent research demonstrates that transfusing whole blood (WB=red blood cells (RBC)+plasma+platelets) rather than just RBC (which is current National Health Service (NHS) practice) may improve outcomes for major trauma patients. As part of a programme to investigate provision of WB, NHS Blood and Transplant undertook a 2-year feasibility study to supply the Royal London Hospital (RLH) with (group O negative, ‘O neg’) leucodepleted red cell and plasma (LD-RCP) for transfusion of trauma patients with major haemorrhage in prehospital settings.Incidents requiring such prehospital transfusion occur randomly, with very high variation. Availability is critical, but O neg LD-RCP is a scarce resource and has a limited shelf life (14 days) after which it must be disposed of. The consequences of wastage are the opportunity cost of loss of overall treatment capacity across the NHS and reputational damage.The context was this feasibility study, set up to assess deliverability to RLH and subsequent wastage levels. Within this, we conducted a quality improvement project, which aimed to reduce the wastage of LD-RCP to no more than 8% (ie, 1 of the 12 units delivered per week).Over this 2-year period, we reduced wastage from a weekly average of 70%–27%. This was achieved over four improvement cycles. The largest improvement came from moving near-expiry LD-RCP to the emergency department (ED) for use with their trauma patients, with subsequent improvements from embedding use in ED as routine practice, introducing a dedicated LD-RCP delivery schedule (which increased the units ≤2 days old at delivery from 42% to 83%) and aligning this delivery schedule to cover two cycles of peak demand (Fridays and Saturdays).

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) was hosted virtually from Philadelphia July 17-21, 2021. The conference, now held annually, highlighted cutting-edge advances in basic, population and clinical sciences of relevance to the Society. Despite being held virtually, the 2021 congress was of the same scope and quality as an annual meeting held in person. An added feature of the program is that talks streamed at the designated times will then be available on-line for asynchronous viewing. The program included 77 State of the Art (SOA) talks, thematically grouped in 28 sessions, given by internationally recognized leaders in the field. The SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. The topics, across the main scientific themes of the congress, include Arterial Thromboembolism, Coagulation and Natural Anticoagulants, COVID-19 and Coagulation, Diagnostics and Omics, Fibrinogen, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostasis in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Angiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the congress. ispartof: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS vol:5 issue:5 ispartof: location:United States status: published

Background Fresh frozen plasma (FFP) is the accepted standard treatment for clotting factor replacement in bleeding patients during or immediately after cardiac surgery. In the United Kingdom prothrombin complex concentrate (PCC) is not licensed in this setting, although it is being used in Europe because it has a higher concentration of clotting factor levels, and it can be administered rapidly and in small volume, resulting in less volume overload during cardiac surgery. Methods PROPHESY is a pragmatic, single-centre, open-label, randomised, controlled pilot trial that will assess whether it is feasible to perform a large trial in the future that will compare PCC versus FFP in patients who are bleeding (not on warfarin) and who require blood transfusion. Over a 15-month period, 50 patients will be randomised to PCC versus FFP if they develop active bleeding within 24 h of cardiac surgery and for whom the clinician has decided to administer FFP for treatment of bleeding. Standard laboratory and point-of-care assessments will be performed as per routine practice, and additional research blood samples will be taken at three time points to assess haemostasis. Subjects will be assessed daily up to hospital discharge or 30 days or death (whichever occurs first) and will be seen in follow-up for 90 days after surgery to assess for thromboembolic complications and hospital re-admission since discharge. Quality-of-life assessment will be performed pre-surgery and at 90 days post-surgery. We will also perform qualitative research with clinical experts and patients to explore the understanding of and experience with the interventions, as well as adherence to study procedures and protocol. Discussion There have been no randomised controlled trials that have compared the safety and efficacy of FFP versus PCC in cardiac surgery patients who are bleeding. This pilot study will assess if individual components of a large trial are deliverable to assess the safety and efficacy of the two blood products in the future. Trial registration EudraCT, 2018-003041-41; ClinicalTrials.gov, NCT03715348. Registered on 29 July 2018.

Objective The aim of this study was to identify the effects of recent innovations in trauma major hemorrhage management on outcome and transfusion practice, and to determine the contemporary timings and patterns of death. Background The last 10 years have seen a research-led change in hemorrhage management to damage control resuscitation (DCR), focused on the prevention and treatment of trauma-induced coagulopathy. Methods A 10-year retrospective analysis of prospectively collected data of trauma patients who activated the Major Trauma Centre's major hemorrhage protocol (MHP) and received at least 1 unit of red blood cell transfusions (RBC). Results A total of 1169 trauma patients activated the MHP and received at least 1 unit of RBC, with similar injury and admission physiology characteristics over the decade. Overall mortality declined from 45% in 2008 to 27% in 2017, whereas median RBC transfusion rates dropped from 12 to 4 units (massive transfusion rates from 68% to 24%). The proportion of deaths within 24 hours halved (33%-16%), principally with a fall in mortality between 3 and 24 hours (30%-6%). Survivors are now more likely to be discharged to their own home (57%-73%). Exsanguination is still the principal cause of early deaths, and the mortality associated with massive transfusion remains high (48%). Late deaths are now split between those due to traumatic brain injury (52%) and multiple organ dysfunction (45%). Conclusions There have been remarkable reductions in mortality after major trauma hemorrhage in recent years. Mortality rates continue to be high and there remain important opportunities for further improvements in these patients.

Current management principles of hemorrhagic shock after trauma emphasize earlier transfusion therapy to prevent dilution of clotting factors and correct coagulopathy. London's Air Ambulance (LAA) was the first UK civilian prehospital service to routinely offer prehospital red blood cell (RBC) transfusion (phRTx). We investigated the effect of phRTx on mortality.Retrospective trauma database study comparing mortality before implementation with after implementation of phRTx in exsanguinating trauma patients. Univariate logistic regression was performed for the unadjusted association between phRTx and mortality was performed, and multiple logistic regression adjusting for potential confounders.We identified 623 subjects with suspected major hemorrhage. We excluded 84 (13.5%) patients due to missing data on survival status. Overall 187 (62.3%) patients died in the before phRTx period and 143 (59.8%) died in the after phRTx group. There was no significant improvement in overall survival after the introduction of phRTx (P = 0.554). Examination of prehospital mortality demonstrated 126 deaths in the pre-phRTx group (42.2%) and 66 deaths in the RBC administered group (27.6%). There was a significant reduction in prehospital mortality in the group who received RBC (P 0.001).phRTx was associated with increased survival to hospital, but not overall survival. The "delay death" effect of phRTx carries an impetus to further develop inhospital strategies to improve survival in severely bleeding patients.

Haemostasis is a complex process that ensures the maintenance of blood flow under normal physiological conditions and prevents major blood loss following vascular injury. The process is tightly regulated to prevent pathological thrombosis. Normal haemostasis relies on the delicate balance of prothrombotic and anticoagulant processes, where five components play a significant role in maintaining the haemostasis, these include: (1) endothelial cells; (2) platelets which are key to platelet plug formation; (3) coagulation factors that are essential to formation of insoluble fibrin clot; (4) coagulation inhibitors; and (5) fibrinolysis. This article will provide an overview of the current concepts of haemostasis, and through this we will explain how antiplatelets and antithrombotic drugs work, as well as provide a basic understanding of how to interpret clotting tests used to measure coagulation disorders.

The lack of antidotes for activated factor X‐inhibitor direct oral anticoagulants (DOACs) means that management of bleeding consists largely of existing supportive therapies. This study aimed to: (i) examine the relative frequency of DOAC‐related major bleeding in relation to DOAC prescriptions over the study period; (ii) describe the presentation and haematological management of DOAC‐related major bleeding; and (iii) evaluate the association between the use of prothrombin‐complex‐concentrate (PCC) and in‐hospital mortality. Over a 3‐year period, 32 UK hospitals submitted data on haematological management of DOAC‐related bleeding. Data consisted of 421 episodes (67%, 21%, 11% and 1% on rivaroxaban, apixaban, dabigatran and edoxaban respectively) of major bleeding on DOACs. The proportion of major bleeds on DOACs and DOAC prescriptions increased throughout the study. Overall, 44% and 37% of patients presented with gastrointestinal bleeding and intracranial haemorrhage (ICH) respectively. Drug concentrations were seldom measured. Compared to no PCC, there was a borderline evidence that receiving low dose PCC (≤25 iu/kg) was associated with better outcomes in terms of mortality (sub‐distribution hazard ratio: 0·15; 95% confidence interval: 0·02–1·19; P = 0·07): but this was not the case for higher doses. DOAC concentrations are seldom measured. There was no evidence of benefit for PCC on in‐hospital mortality.

There are no estimates of the heritability of phenotypic udder traits in suckler sheep, which produce meat lambs, and whether these are associated with resilience to mastitis. Mastitis is a common disease which damages the mammary gland and reduces productivity. The aims of this study were to investigate the feasibility of collecting udder phenotypes, their heritability and their association with mastitis in suckler ewes. Udder and teat conformation, teat lesions, intramammary masses (IMM) and litter size were recorded from 10 Texel flocks in Great Britain between 2012 and 2014; 968 records were collected. Pedigree data were obtained from an online pedigree recording system. Univariate quantitative genetic parameters were estimated using animal and sire models. Linear mixed models were used to analyse continuous traits and generalised linear mixed models were used to analyse binary traits. Continuous traits had higher heritabilities than binary with teat placement and teat length heritability (h2) highest at 0.35 (SD 0.04) and 0.42 (SD 0.04), respectively. Udder width, drop and separation heritabilities were lower and varied with udder volume. The heritabilities of IMM and teat lesions (sire model) were 0.18 (SD 0.12) and 0.17 (SD 0.11), respectively. All heritabilities were sufficiently high to be in a selection programme to increase resilience to mastitis in the population of Texel sheep. Further studies are required to investigate genetic relationships between traits and to determine whether udder traits predict IMM, and the potential benefits from including traits in a selection programme to increase resilience to chronic mastitis.\ud \ud

Traumatic haemorrhage remains a major cause of preventable death and early haemostatic resuscitation is now a mainstay of treatment internationally. Recently, 2 randomized control trials (RCTs) - PAMPer (Prehospital Air Medical Plasma) and COMBAT (Control of Major Bleeding After Trauma), evaluating the effect of pre-hospital use of plasma on mortality provided conflicting results, raising important questions on the role of plasma resuscitation in pre-hospital environment. Both PAMPer (n = 501 patients) and COMBAT (n = 144 patients) trials were pragmatic RCTs that evaluated the effect of pre-hospital plasma transfusion (two units) versus standard of care on 28/30 days mortality in trauma patients who presented with clinical signs of haemorrhagic shock (defined as hypotension or tachycardia). The PAMPer trial showed that plasma transfusion reduced 30-day mortality compared with standard of care (23% vs 33%, 95% confidence interval -18.6; -1.0%; P = 0.03), while COMBAT trial showed no difference in 28-day survival. The post-hoc analyses of the 2 trials have suggested that the benefit of pre-hospital plasma transfusion may be greater for patients who are coagulopathic, have blunt injury and have a transport time from the scene of injury to the hospital of >20 minutes. In this review we evaluate strengths and limitations of the two trials and their differences and similarities, which may explain the conflicting results, as well as provide directions for future trials to better define the target population that would most benefit from pre-hospital plasma resuscitation. Further, considering the logistical challenges of carrying any blood components on an aircraft, cost/safety of plasma, and the scarcity of universal blood group donors, there is a need for a health economic evaluation of pre-hospital plasma transfusion in trauma patients, prior to this intervention becoming universal.

BackgroundPre-hospital blood component transfusion poses logistical challenges. Current patterns of pre-hospital blood use across the UK are not known. A potential benefit of providing a single combined component of whole blood is reduced need for multiple steps of administering separate components and more efficient use of time and resources by medical staff. .Objectivesto undertake a detailed time-analysis of the steps of pre-hospital combined component transfusion against separate blood component transfusion, and to determine current UK pre-hospital transfusion practice and users’ optimal pre-hospital transfusion strategyMethodsA three-arm cross-over major haemorrhage simulation study compared: flow-time (time from decision-to-transfuse [DTT] to complete transfusion); touch-time (direct team ’hands on’ contact time with transfusion process); and number of steps, people and equipment required for transfusion of 2 units of RCP [arm-A], 2 RBC + 2 TP [arm-B] or RBC + 2 Lyoplas [arm-C]). A national survey of current and optimal pre-hospital transfusion strategies was sent to 22 UK Air Ambulance Services (AAS) and 27 Major Trauma Centres (MTC) in December 2019. ResultsThe simulation demonstrated that arm-A had a shorter flow-time (median 6min 31sec vs. 12min 20 sec, vs 16min 29 sec) and touch-time (median 2min 31 seconds vs. 5min 21sec vs. 15min 3sec) than arm-B and arm-C respectively, and required fewer steps, equipment and checks. 18 MTCs and 18 AAS responded to the national survey (response rates of 67 and 82%). 10 transfused RBC/plasma (5 TP/5 Lyoplas), 4 RBC only, 2 Lyoplas only, 1 RBC/Lyoplas/Fibrinogen, and 1 ’red cell and plasma’ (only available at one hospital site). 89% replied that a combined component transfusion would be desirable, as it would reduce patient mortality (83%) and tasks on scene (75%). ConclusionThe time-analysis established the benefits for combined pre-hospital component transfusion in trauma patients. The national survey demonstrates the variation in current pre-hospital transfusion practice and reiterates that combined component transfusion pre-hospital may have logistical advantages over separate components.

Background\ud The association between international-normalised-ratio (INR) correction and mortality in patients with major bleeding on vitamin-K-antagonists (VKA) is important for evaluating the efficacy of reversal agents for oral anticoagulants.\ud \ud Objectives\ud We evaluate if INR correction (defined as ≤1.3) following intervention in major bleeding on VKA is associated with better survival, and if there is a dose-response relationship between Vitamin K (VK) and INR correction.\ud \ud Methods\ud Data on patients' characteristics, haematological management and 30-day outcomes reported by 32 UK hospitals (October 2013–August 2016) were analysed. Associations between INR correction and: (a) 30-day mortality; (b) VK dose were estimated using multivariable logistic regression, using multiple imputation to handle missing INR values.\ud \ud Results\ud Of 1771 patients, 77%, 73% and 33% received prothrombin-complex-concentrate (PCC), VK (92% intravenous) and red cells and fresh frozen plasma transfusion respectively. Proportionally more intracranial haemorrhage (ICH) cases (87%) than non-ICH cases (69%) received PCC. VK administration did not vary by ICH group, with 10 mg (33%) and 5 mg (28%) doses being the most common. Higher doses of VK (10 mg) were more likely to correct INR than lower doses (5 mg). Post-intervention INR > 1.3 in treated patients was associated with 3.2 (95%CI: 2.1–4.9) times higher odds of death within 30 days, compared with INR ≤ 1.3, with no difference between ICH and non-ICH.\ud \ud Conclusions\ud INR correction after intervention to manage major bleeding on VKA is associated with better survival. Higher VK doses (10 mg) improve INR correction more than lower doses (5 mg) in major bleeding, but further studies are warranted to compare the relative benefits/risks of 5 mg versus 10 mg doses.

Highlights • Multiple model triangulation identifies variables that are likely true positives. • Triangulation increases confidence in which managements to recommend in practice. • Effective management of ewes can lower prevalence of lameness in ewes and lambs., Identification of factors associated with an outcome can be challenging when the number of explanatory variables is large in relation to the number of observations. Multiple model triangulation, where results from several model types are combined, improves the likelihood of identifying true predictor variables. The aim of this study was to use triangulation to identify covariates likely to be truly associated with the prevalence of lameness in sheep flocks in Great Britain. Data were collected using a questionnaire sent to 3200 sheep farmers in Great Britain in 2018. The useable response rate was 14.1 %. The geometric mean prevalence of lameness was 1.4 % (95 % CI 1.2−1.7) for ewes, and 0.6 % (95 % CI 0.5−0.9) for lambs, however, approximately 60 % flocks had >2% prevalence of lameness in ewes. Four model types were investigated, two generalised linear models (negative binomial and quasi-Poisson) built using stepwise selection, and two elastic net models (Poisson and Gaussian distributions) refined with selection stability estimation. Triangulated covariates were those selected in three or all four models – 10 for ewes and 12 for lambs. Higher prevalence of lameness in ewes was associated with 5−100% feet bleeding during routine foot trimming compared with not foot trimming, footbathing the flock to treat severe footrot (SFR) and always using formalin in footbaths, both compared with not footbathing, using FootVax™ for 3 weeks compared with always. Lower prevalence of lameness in ewes was associated with vaccinating with FootVax™ for >5 years compared with not vaccinating, peat soil compared with no peat soil, and having no lame ewes to treat. Higher prevalence of lameness in lambs was associated with 5−100% feet bleeding during routine foot trimming, always foot trimming ewes with SFR, not knowingly selecting replacement ewes from ewes that were never lame compared with always, replacement sheep purchased and homebred compared with only homebred, treating lambs >3 days after recognition of lameness compared with 0-3 days and footbathing the flock to treat interdigital dermatitis compared with not footbathing at all. Lower prevalence of lameness in lambs was associated with peat soil, flocks in Scotland versus England, an altitude of >230−500 m compared with ≤230 m, never using antibiotic injection to treat lambs with SFR compared with always, and having no lame lambs to treat. We conclude triangulation identified reliable management practices for farmers to implement to minimise lameness in sheep.

Dichelobacter nodosus is the essential pathogen in ovine footrot, an important cause of lameness in sheep that reduces productivity and welfare. The aim of this study was to investigate the feasibility of using multiple locus variable number tandem repeat analysis (MLVA) developed to investigate isolates to understand the molecular epidemiology of Dichelobacter nodosus in ovine footrot by investigation of communities of strains. MLVA sensitivity was improved by optimizing PCR conditions to 100% specificity for D. nodosus. The improved MLVA scheme was used to investigate non-cultured DNA purified from swabs (swab DNA) and cultured DNA from isolates (isolate DNA) from 152 foot and 38 gingival swab samples from 10 sheep sampled on four occasions in a longitudinal study. Isolate DNA was obtained from 6/152 (3.9%) feet and 5/6 yielded complete MLVA profiles, three strains were detected. Two of the three isolate strains were also detected in isolate DNA from 2 gingival crevice cultures. Complete MLVA profiles were obtained from swab DNA from 39 (25.7%) feet. There were 22 D. nodosus community types that were comprised of 7 single strain and 15 multi-strain communities. Six community types were detected more than once and three of these were detected on the same four sheep and the same two feet over time. There were a minimum of 17 and a maximum of 25 strain types of D. nodosus in the study. The three isolate strain types were also the most frequently detected strain types in swab DNA. We conclude that the MLVA from swab DNA detects the same strains as culture, is much more sensitive and can be used to describe and differentiate communities and strains on sheep, feet and over time. It is therefore a sensitive molecular tool to study D. nodosus strains directly from DNA without culture.

The evidence base for management practices associated with low prevalence of lameness in ewes is robust. Current best practice is prompt treatment of even mildly lame sheep with parenteral and topical antibiotics with no routine or therapeutic foot trimming and avoiding routine footbathing. To date, comparatively little is known about management of lameness in lambs. Data came from a questionnaire completed by 1,271 English sheep farmers in 2013. Latent class (LC) analyses were used to investigate associations between treatment of footrot and geometric mean flock prevalence of lameness (GMPL) in lambs and ewes, with multinomial models used to investigate effects of flock management with treatment. Different flock typologies were identified for ewes and lambs. In both ewe and lamb models, there was an LC (1) with GMPL 10% of lambs were lame, while farmers were likely to use parenteral antibiotics, only sheep with locomotion score >2 were considered lame, leaving lame sheep untreated, potentially allowing spread of footrot. These farmers also used poor practices of routine foot trimming and footbathing, delayed culling, and poor biosecurity. We conclude there are no managements beneficial to manage lameness in lambs different from those for ewes; however, currently lameness in lambs is not treated using “best practice.” In flocks with

Summary There is equipoise regarding the use of prothrombin complex concentrate vs. fresh frozen plasma in bleeding patients undergoing cardiac surgery. We performed a pilot randomised controlled trial to determine the recruitment rate for a large trial, comparing the impact of prothrombin complex concentrate vs. fresh frozen plasma on haemostasis (1 h and 24 h post‐intervention), and assessing safety. Adult patients who developed bleeding within 24 h of cardiac surgery that required coagulation factor replacement were randomly allocated to receive prothrombin complex concentrate (15 IU.kg−1 based on factor IX) or fresh frozen plasma (15 ml.kg−1). If bleeding continued after the first administration of prothrombin complex concentrate or fresh frozen plasma administration, standard care was administered. From February 2019 to October 2019, 180 patients were screened, of which 134 (74.4% (95%CI 67–81%)) consented, 59 bled excessively and 50 were randomly allocated; 25 in each arm, recruitment rate 35% (95%CI 27–44%). There were 23 trial protocol deviations, 137 adverse events (75 prothrombin complex concentrate vs. 62 fresh frozen plasma) and 18 serious adverse events (5 prothrombin complex concentrate vs. 13 fresh frozen plasma). There was no increase in thromboembolic events with prothrombin complex concentrate. No patient withdrew from the study, four were lost to follow‐up and two died. At 1 h after administration of the intervention there was a significant increase in fibrinogen, Factor V, Factor XII, Factor XIII, α2‐antiplasmin and antithrombin levels in the fresh frozen plasma arm, while Factor II and Factor X were significantly higher in the prothrombin complex concentrate group. At 24 h, there were no significant differences in clotting factor levels. We conclude that recruitment to a larger study is feasible. Haemostatic tests have provided useful insight into the haemostatic changes following prothrombin complex concentrate or fresh frozen plasma administration. A definitive trial is needed to ascertain the benefits and safety for each.

Fibrinogen is a critical coagulation protein involved in both primary and secondary hemostasis. Cryoprecipitate preparation was first described by Dr. Judith Graham Pool in 1964 at Stanford University as a product for factor VIII replacement in patients with hemophilia A. Its use for hemophilia A has been superseded by safer, virally inactivated recombinant products. At the present time, cryoprecipitate is only used for fibrinogen replacement for patients with acquired bleeding disorders and hypofibrinogenemia. The product also contains fibrinogen, von Willebrand factor, fibronectin, factor XIII, and platelet microparticles. The hemostatic contribution of these other hemostatic factors in the management of the trauma patient is unknown. Each 10-unit pool must contain typically at least 1.5 g (150 mg per unit) of fibrinogen by regulatory requirements, although may contain substantially more due to donor variability. In contrast, fibrinogen concentrate is a heat-treated, lyophilized fibrinogen powder made from pooled human plasma which must be reconstituted with water prior to injection. Each vial contains between 900 and 1300 mg fibrinogen, as well as 400 and 700 mg human albumin. Hypofibrinogenemia is common in trauma patients on arrival ( 1.5–2.0 g/L). A large clinical trial in trauma hemorrhage to access the effects of early high dose fibrinogen replacement with cryoprecipitate on survival is currently in progress. While we await better evidence on when and how cryoprecipitate should be used, it is reasonable to administer cryoprecipitate if the fibrinogen is under 2 g/L and the patient has serious ongoing hemorrhage. A dose of 10 units (or 50 mg/kg of fibrinogen in pediatrics) or equivalent does of fibrinogen concentrate (4 g) is a reasonable starting dose as such patients will typically be receiving some fibrinogen replacement with each bag of plasma.

We present the largest and most representative study of the serological diversity of Dichelobacter nodosus in England. D. nodosus causes footrot and is one of the top five globally important diseases of sheep. The commercial vaccine, containing nine serogroups, has low efficacy compared with bivalent vaccines. Our aim was to investigate the prevalence and distribution of serogroups of D. nodosus in England to elucidate whether a bivalent vaccine could protect the national flock. Farmers from 164 flocks submitted eight interdigital swabs from eight, preferably diseased, sheep. All serogroups, A–I, were detected by PCR in 687/1150 D. nodosus positive swabs, with a prevalence of 2.6–69.3% of positive swabs per serogroup. There was a median of two serogroups per flock (range 0–6). Serogroups were randomly distributed between, but clustered within, flocks, with 50 combinations of serogroups across flocks. H and B were the most prevalent serogroups, present in > 60% of flocks separately but in only 27% flocks together. Consequently, a bivalent vaccine targeting these two serogroups would protect 27% of flocks fully (if only H and B present) and partially, if more serogroups were present in the flock. We conclude that one bivalent vaccine would not protect the national flock against footrot and, with 50 combinations of serogroups in flocks, flock-specific vaccines are necessary.

IntroductionThe incidence of severe postpartum haemorrhage (PPH) that requires blood transfusion is on the increase. Fibrinogen levels have been shown to drop early and significantly during PPH, which is associated with worse outcomes. Early fibrinogen replacement could potentially improve outcomes. No studies have investigated the clinical impact of early cryoprecipitate transfusion in PPH. Prior to performing a full-scale trial, a pilot study is needed to determine feasibility of the intervention and recruitment.MethodsACROBAT is a cluster-randomised pilot study with a qualitative evaluation. Four large London maternity units are randomised to either the intervention or control group. The intervention group will adapt their major obstetric haemorrhage procedures to administer cryoprecipitate early for primary PPH. The control group will retain their standard of care.We include women at >24 weeks gestation who are actively bleeding within 24 hours of delivery and for whom transfusion of red blood cells (RBCs) has been started. We exclude women who decline blood transfusions in advance or have inherited Factor XIII or fibrinogen deficiency. Due to the emergency nature of the intervention, informed consent for administering the intervention is waived.The primary objective is to assess the feasibility of administering cryoprecipitate within 90 min of RBC request, as compared with standard treatment where cryoprecipitate is given later or not at all. Secondary objectives include the feasibility of recruitment and data collection, reasons for and barriers to consent, preliminary maternal clinical outcomes, identification of the optimal infrastructure pathways for study delivery, and acceptability of the intervention and outcomes.Ethics and disseminationThe trial has approvals from the London—Brighton & Sussex Research Ethics Committee (ref. 18/LO/2062), the Confidentiality Advisory Group (ref. 18/CAG/0199) and Health Research Authority (IRAS number 237959). Data analysis and publication of manuscripts will start in Q3 2020.Trial registration numberISRCTN12146519.

Prolonged aPTT in Patients with Covid-19 In this study, 20% of patients with Covid-19 had a prolonged activated partial-thromboplastin time. In 90% of these cases, the cause was lupus anticoagulant...

Introduction The benefit of administering chemical thromboprophylaxis to chronic kidney disease patients undergoing renal transplantation is unclear and no previous systematic review has addressed this as reflected by variations in national guidelines. Methods A literature search was performed using MEDLINE, Embase, Cochrane, CINAHL, World Health Organisation (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov databases to December 2019. Studies included participants undergoing renal transplantation only with no contra-indication to thromboprophylaxis, no history/clinical suspicion of acute organ rejection and those describing a form of chemical thromboprophylaxis intervention compared with another form, no intervention or placebo. Results Thirteen studies with 1600 patients were included. There was wide variation concerning type of thromboprophylaxis, time of onset, dosing and duration. Reports of symptomatic/asymptomatic venous thromboembolism and mortality were limited. Seven studies reported on renal allograft thrombosis. When comparing thromboprophylaxis to no intervention, there was no evidence of difference for thrombosis risk (risk ratio 0.2; [95% CI 0.01–4.63]), however all studies were underpowered to answer this question. Six studies reported on major bleeding but type of intervention, timing of onset and duration of thromboprophylaxis varied significantly, making it difficult to pool data for further analysis. Conclusion There is insufficient evidence to advise on efficacy and safety of chemical thromboprophylaxis in patients undergoing renal transplantation or to determine whether one chemical thromboprophylaxis is better than another thromboprophylaxis.

Twenty-nine farmers with a flock prevalence of lameness >5% were visited in 2013. They participated in a facilitated discussion on treatment of footrot, and evidence-based new “best practice.” One year later, farmers were revisited and management and motivators for change were discussed. Farmers were asked how they would persuade other farmers to adopt “best practice.” Initially, most participants were resigned to having lame sheep. They believed that prototypical “good farmers” (including trusted family) practiced foot trimming, the traditional “best practice” and that the new “best practice” would be expensive and time consuming. Between 2013 and 2014 lameness prevalence reduced from 7.6 to 4.3%. The major behavioral changes were reduction in foot trimming, increased use of antibacterials to treat footrot, and treating sheep within a week of becoming lame. In 2014, participants were re-interviewed. They reported that an increased knowledge of the evidence-base, trust in the facilitator and talking to other trusted farmers who had already adopted the new “best practice” overcame concerns about the prototypical “good farmer” and motivated change. Persistent change occurred because participants observed health benefits for their sheep and that the new “best practice” had saved time and money. Participants stated that other farmers would be convinced to change to the new “best practice” because it saved time and money, ironically, these were among the original barriers to change. This is possibly an example of cognitive dissonance because farmers had become positive about the benefits of saving time and money following a change in their own behaviors.

We use the concepts of trust and knowledge to explore translation of scientific evidence about treatment of ovine footrot to students studying at agricultural colleges. We explore the role of different forms of trust (companion, competence and commitment) in facilitating relationships between students and informants. We also investigate how students acquire knowledge, and how this influences their practices for treating footrot. We find that despite being taught evidence-based practice (antibiotic treatment and no foot trimming) at college, most students would still use traditional farm practice (foot trimming) to treat footrot. Students develop tacit knowledge of traditional practices from farmers whilst working on sheep farms and these farmers have a strong influence on students' practices; students have high levels of companion trust for “known farmers". College lecturers who demonstrate competence gain students' trust, but where this does not occur there is a failure in communication between lecturer and student. Students acquire explicit classroom knowledge of evidence-based practice at college because there is limited practical experiential learning. This explicit knowledge is typically insufficient to change behaviour, unless students trust their lecturer. Our findings indicate that farming experience dominates over classroom experience and so college education alone will not ensure uptake of evidence-based practice.